What promise do stem cells hold for the treatment of medical conditions? In this five-part online course you will explore the history and basic biology of stem cells, learn about new research techniques, and find out how stem cells could lead to cures for diseases and to individualized medicine. You will hear from Museum scientists, medical researchers at the frontiers of the field, and a panel of bioethics experts who will address the ethical implications of stem cell research and therapy. Learn what has already been accomplished, what challenges remain, and what medical breakthroughs may lie ahead.

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DR

Excellent, well presented course. The content was difficult and I reviewed some of the videos several times, even with a science background. I highly recommend this!

JB

Jan 23, 2019

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Excellent course. Good teachers. I was especially charmed by the panel discussion. I was able to learn the course material easily. Very interesting and up to date.

From the lesson

Using Stem Cells to Treat Disease

In addition to the great potential of stem cells to be used in the study of disease, stem cells can also be used to actually treat disease. Neural stem cell pioneer Dr. Sally Temple will explain the potential for using stem cells in our own bodies (adult stem cells) to treat age-related macular degeneration, an increasingly common and debilitating disease. Dr. Temple will also give you some tools for evaluating potential stem cell treatments.

Taught By

Dr. Zehra Dincer

Course Instructor

Transcript

We've already heard a lot about the difference between pluripotent and adult stem cells. Pluripotent stem cell can give rise to any tissue in the body. Any of those 200 and odd cells. And so they're very powerful and they're very useful for making tissues that don't normally have regenerative potential. At the same time, we have adults or tissue derived or somatic stem cells that means the same thing. And these ones are derived from different tissues and they're specialized to give cells of that tissue. Here are some examples of the tissue-specific stem cells. If you go into the brain, there are a few places you can find stem cells in the brain, they're actually important for memory formation. There are stem cells in skeletal muscle, if you damage the muscle, it has the power to regenerate. Bone marrow, we heard a lot about, and the gut. But there are other tissues that really don't have very much regenerative potential. For those you need to use that pluripotent stem cells. But for these tissues you have a lot of potential right there in your own body. As you are reading about stem cell therapies, you might come across two words that I thought are really important that to address this issue. Autologous. That means it's a stem cell from your body. And because it's from your body, it most likely will not be rejected. So, in contrast, allogeneic. That means it's from some other person and unless it's an identical twin, these have the risk of being rejected. And it turns out that every cell in each of us has a unique barcode. The HLA proteins it's different from every individual unless you're an identical twin, and there are immune cells that survey around the body that go everywhere and they're looking out to see if the cell has got the self barcode or the non-self barcode. And if it's non-self, then the immune cells can attack it which is why you need to be on immunosuppressive therapies if you have an allogeneic transplant. This though, is really in development because you have the potential of taking healthy cells from one donor and then putting them into a different donor. And so immunosuppression is one of the things that we have to cope with right now. Ultimately, if we can use the induced pluripotent stem cells, we may be able to get away from that and use personalized stem cells in the future. But right now, these are two words that you might come across in your reading. So, it's very exciting. There's a lot of stem cells being developed for therapies. And within these adult stem cells, the ones that are restricted to giving just a few cells, you can see that there are many different diseases that these stem cells are valuable for. In some cases, they're already in the clinic. For people who have corneal burns for example, you can use what are called limbal stem cells which come from the edge of the cornea, and if you've been burnt in one eye you can take the limbal stem cells from the cornea in the other eye and move it across and they will take and they will make a beautiful clear cornea for these patients, completely changing their quality of life, being able to see from two eyes. There's quite a lot of work developing nervous systems stem cells for spinal cord injury or ALS for example. So we are on the lookout for applications for all of these different cell types coming along in the clinical process. So I want to talk about the work that we do up in Albany. We have a team of people performing this work and it's led by me but also my husband, Jeff Stern who's over here and who is a Vitreo-Retinal surgeon as well as a researcher. So brings that clinical perspective which is so important when you're moving towards a clinical trial. So the disease that we work on is age-related macular degeneration. It's a very common neurodegenerative disease and it actually affects one in five people over age 75. It's getting even younger, it's moving younger in the population. What happens in this disease is that there's a special cell type in the back of the eye called the retinal pigment epithelium, actually we can see it, if you look in someone's eyes at the pupil and you look inside you see black. That black is the pigmented layer mostly contributed by the retinal pigment epithelium. It's part of the nervous system. These cells are very important, they actually help replenish the photoreceptors which are the light responsive cells in the eye. So when light comes in, these cells, the photoreceptors, respond and when they respond, they actually use up some chemicals that have to be replaced every day. And the retinal pigment epithelium which is this layer of cells does that. So in patients with macular degeneration, what happens is, they start to build up these abnormal accumulations under the retinal pigment epithelium. They're called drusen. They actually have some of the molecules that you also find in Alzheimer's disease. So, the build up of these drusen is rather similar, and thought to have a similar shared mechanism. So these drusen can be seen if you go have a picture taken of the back of the eye, the doctor may see these little white or yellow spots in the back. And they tend to be in the central part of the retina. And that's really unfortunate because that's exactly the part that we use to see. It's where we have color vision, it's where we have high acuity vision. So, if you have this, then your sight instead of being normal will be perturbed, will fade, and eventually there'll be a big black spot everywhere you look. So patients with this can no longer read or recognise faces, it robs you of your independence. And it's really an awful thing. My mom had it so I know personally how difficult it is and I would just ask you to take a minute to think about the impact on your life if you could not read the simplest thing. So currently, for this form of the disease which is called the dry form and there are about 85 percent of the people in the US have this dry form, no therapies are available, you're told to take vitamins which of course have very limited effect. If you're vitamin deficient they probably help you, but otherwise, rather limited effect. So, here is that special layer of cells and it's unusual being a central nervous system cell with actually a simple monolayer. Most central nervous system cells have got very long interconnected processes, form a huge network. So in reality, this is like a thin carpet and it may be easier to think about how we can replace and repair cells in a carpet versus having all of those long projections. So it's been a very popular target for stem cell therapy. We can make the cells in the culture dish by coaxing them down the pathways that you heard about today. To take a cell it can make anything and turn it just into the retinal pigment epithelium. That's one way to make the cells. The other, is to look for an adult stem cell that can make retinal pigment epithelium and then use these cells to replace those cells that are damaged in patients by injecting them into that location. So, Geoff, Stern, and others in the lab helped really formulate the idea for this. What we do is, we take adult cadaver eyes. So, patients who donate their eyes to eye banks when they pass away, which is a phenomenal and generous thing to do. The front part of the eye, the cornea can get transplanted and give sight to individuals. The back part of the eye gets thrown away. And that's the part that we want. So, we actually recover that back part and we take out these pigmented layer of cells. So, here in this image, it's very high powered, that's one cell, that's another cell. You can see the little dots of pigment, you could see it's a simple monolayer like a carpet. So, we take these out, these cells. We put them in tissue culture, and we give them growth factors that helps them divide. So, you see all of these pigmented cells. That's one cell, that's another cell, another cell. After about 12 days, having been given the growth factors, what we see as little nests of cells appearing. You'll see that different because at this point, they're not pigmented, they're also proliferating. By seven weeks, they've taken over the whole culture. And these are new stem cells. These are the what we've termed, retinal pigment epithelial stem cells. So, we were extremely excited when we discovered these cells. It turns out that we have regenerative power in our eye. So, having discovered them, we said, what what can we do? How can we use them? What we wanted to do was to use them to replace those lost cells in AMD. And in order to do that, we had to scale up. We had to make enough cells to be able to use in many different patients. And that required us to scale up, have the cells grow, but maintain that normal carpet, which looks actually like a cobblestone. I think you can see a cobblestone morphology. So, we had to invent a new culture medium because the one on the market, made the cells look like this, like fibroblast instead of like cobblestones. So, I can show you here what it looks like. As we grow the cells, you can see the cells are dividing. But what you'll notice here, is that they begin to produce little barriers between the cells. It looks almost like a sort of animal coat, if you can see that. Being able to produce that cobblestone was absolutely critical. So now, we can make the cells at scale. We have a cell source that is really wonderful. There are a hundred thousand donations every year to eye banks, and we can take that back part of the eye that no one wants. Expand them and tissue culture. And then, the idea here is that, we can transplant those into the Macular, the central part of the retina, where the cells are dead or dying in patients. And we want to put them in before the photoreceptors have died. So, photoreceptors are still there, but the retinal pigment epithelium is damaged. So, how do you take an idea, a concept into the clinic? We learned, having done this for the first time, this really is a long road. It's very different from research that you do in the laboratory normally, which is you make a discovery and then you move on to something else. Here, you have to pay attention to every single detail. The FDA wants to know every reagent that you're going to use. Have you screened the donors? You don't want the donor to have viruses like Hep C or HIV. You got to screen that. You've got to make sure that the process is compatible with regulations. And then, you have to test the cells in animal models to see if they work. That's efficacy. And to see if they're safe. So, you have to do a safety or toxicology set of experiments as well. So, we had to create a cell manufacturing at the clinical grade, that's going on at the University of Rochester. We had to do the safety study that's going on in MPI Research in Kalamazoo. We went out to Kalamazoo and injected 300 rats sub-retinaly in order to test whether these are Kalamazoo, Michigan, is a fabulous place to visit in January. I'm just gonna say that. And it all went well. And I say that coming from Albany, but. And then in our lab, we have performed the efficacy studies to show that the cells work. We are working with a team from University of Michigan and also Southern California to make a clinical plan. Ultimately, this huge package will get submitted to the FDA. The FDA then reviews it, and they give you a response. Can you go into the clinic or do you have to wait and go back and do some additional things. We don't want that to happen, but it could happen. So I'm going to ask you, how long do you think it takes the FDA to get back to you, once you've submitted your application to tell you whether or not you can move ahead? Three years, two years, four years, 30 days. 30 days, yes. They have to. This takes a long time. But at this point, they have 30 days and they get back to you. And you hope that they allow you to move ahead. And then you move into a safety trial, a phase one trial. Small number of patients maybe 10. From there, into efficacy, which is going to have a few more patients in. And then, a lot of patients in the phase three. Here's what we learned about this whole process. It is difficult and it is expensive. It's expensive. So for our safety study, which we're only doing on rats, it cost two million dollars. The clinical trials, multi million. And it's up to us to raise the money. That is very hard. That's a big burden for scientists to do it. I mean, you really need to have partners to do this. But, I think it's really worthwhile for scientists to be engaged because we know ourselves, and then working with clinicians who know their patients, and then working with government or investors who are prepared to really help accelerate this process. So, let's look at the proof of concept. And this is very very important. Will your cells work to rescue vision in an animal model? We use the Osseous rat. And yes, they are cute. I'm sorry. These poor rats have a mutation, which means that they go blind. They have a mutation that means their retinal pigment epithelium won't phagocytosin, eat up and renew the photoreceptors that I told you about. That's a really important function. So, the RPE is there, but it doesn't work. And here's an animal that's perfectly normal. And what you'll see is that, there's little thin layer, there is the Retinal Pigment Epithelium. These are photoreceptors, cell bodies. These are the outer segments of the photoreceptors. And you will seen in a normal animal this is very thick. But in this animal, because it can't phagocytos and chew up the photoreceptors properly, you end up losing all of those photoreceptors, there's just one little thin layer. So what we did was transplant in our cells sub-retinaly. And say, can we stop that disease process? So, here are the cells that we transplanted. This is a little clump, they can also distribute as a layer. But, what I want you to see, are those photoreceptors that are lost without the cells. When we put the cells in, they're maintained, and in this example as well. So, we can rescue the anatomy of these cells, of these animals, and that is hard to see, but it's showing you a thin layer. So, we've rescued the anatomy, which is fabulous. But what if that's it? What if the animals can't see any better? So, we have to test the vision on these rats. So what we do is we take the rat and we put it in a chair and we show it an eye chart. And yeah, that actually, doesn't work. That doesn't work. So, you have to use the different track. And in our case, what we did was use the invention by our collaborator on this project. This is actually four monitors. So, it's making almost like a little room. Inside of it there's a platform, and you can put your mouse or rat on this platform. And then, these monitors have balls that go around and circulate. And as a reflex, the animal will follow if it can see. If it can't see, it won't. And if you alter how thick and thin those balls are, you can get to the point where it can't see anymore, and that's a threshold that illustrates how well it can see. And I think, Jeff, that it's the same principle that you use for babies. So, here I think you can see the head is moving with the grid. So, that animal is seeing the movement of the grid, and it's moving in the direction you seeing. So it's subtle, but it's real, and if that doesn't happen. And we have to do these experiments in a what they call a masked fashion, so that the person who's looking at the video looking at the right does not know if that animal has been treated or not. And then, at the end of it, you unmask it, so that you figure out whether or not there was a real difference. So, what we found was that there was a real difference in vision, that if you put the cells in, the visual acuity is high, this is normal vision. Whereas if there's no cells put in there's the animal, by 90 days it can no longer see. The vehicle can have some benefit in itself, but the cells are what really keep it high. So, we've been able to stop that degenerative process in the animal, and that's really key for moving ahead into the clinic. So, as I said, we've made quite a bit of progress. We've got clinical grade cells being made, we've got a proof of concept that this works in animals, the safety study is going on in Kalamazoo, and Jeff has been working with our clinical partners to write that clinical study plan that the FDA will remove. And hopefully, we will get all this together in next year, and submit it, and please everybody, fingers crossed, that 30 days later we get good news. So, we're not certainly the first people to think about a stem cell transplant for age related macular degeneration. There are other people that have been using these pluripotent stem cells, the embryonic, and the induced. The challenge there is that those cells can make everything. So, how do you ensure that they only make the retinal pigment epithelium? You have to put in a lot of growth factors, and cytokines, and do it at the right timing, and eventually you will end up with cells. The cells though are very immature. When you start with these sources they don't make a mature cell, they make a self fetal stage cell. You can implant them and you hope that they continue their maturation afterwards. But we still don't know exactly if that will happen. The cells that we work on are already poised to make RPE, and they may quite mature RPE that can phagocytoes. So, I think that in considering the different sources, we're excited that we will hopefully have the opportunity to test this adult RPE cell, and really compare it. And we all know that for some patients, one approach might be better than another. We don't just have one antibiotic. We have different ones for different patients and different scenarios. So, having options and choices of different stem cells for the same disease target is really beneficial. But the big difference between these cells, the adult RPE stem cells and the others, is that it was present in the eye. And if you think about it, what I said was, we take cadaver eyes, we take the cells out, we grow them out, and then we put them back in. But if they're already there, why not just try to activate them in the eye, before we hit the surgery. So, here's the idea instead of doing what I've just been talking about with the transplant which we're moving ahead with, why not try to activate them? And what we have to do is to figure out what goes in that syringe. But if we can find that, and we have a few candidates, then we could perhaps activate the stem cells inside chip. And this is going to be much easier. This procedure could go on in any retina doc's office, providing we know it's safe and effective, it would be more easily adoptable and easier for patients because you wouldn't have to take the immunosuppressive therapies. So, the inspiration for this approach actually comes from animals like the Salamander which you'll see elsewhere in the museum. In the Salamander, if you remove the neural retina, and you leave behind the retinal picking epithelium, that layer can actually regrow an entire new retina over this four week period. So, you see here it is without a retina, and then gradually it builds up and it grows. Pretty remarkable. So, this is our goal. And finally, what I've described today the work that we do is very much a team effort. There's not one individual person or lab, this is an international collaborative effort. And it's my honor really to represent the work of all these individuals and their labs. Thank you.

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